Quinidine polymanuronate

ABSTRACT

Method for preparing a salt of polymanuronic acid and quinidine by reacting polymanuronic acid or a salt thereof with quinidine or a salt thereof at 70*-75*C in a solvent until the pH of the reaction solution is about 7.

United States Patent Cobo Barrachina July 1, 1975 [54] QUINIDINEPOLYMANURONATE 2,959,583 11/1960 DOCZi 260/209 R [75] Inventor: GonzaloCobo Barrachina, Madrid,

spam Primary Examiner-Johnnie R. Brown 73] A ignee; L b -m i Berenguer Bm Attorney, Agent, or FirmWenderoth, Lind & Ponack S.A., Madrid, Spain[22] Filed: Dec. 8, 1972 211 App]. No.2 313,264 [571 ABSTRACT Method forpreparing a salt of polymanuronic acid Cl 260/209 2 80; 260/21 I R andquinidine by reacting polymanuronic acid or a salt [5|] Int. Cl C07g3/00 h f with quinidine or a salt thereof at 70 75C i [58] held ofSearch 260/209 21 1 209 a solvent until the pH of the reaction solutionis about 7. [56] References Cited UNITED STATES PATENTS 12 Claims, 12Drawing Figures 2,520,255 3/1950 Peterman 260/210 R PHEMTFMHU ms 13892.728

SHEET 1 FIG-1 FIG-1a aar'FEHTEU JUL T 1915 I l9 8 9 2 7 2 8 SHEET 2 o lI 1 200 1000 e00 525 FIG -1 b o I l l 4000 e500 3000 2500 2000 FIG-2 suma 2000 who who 11:00 1500 FIG-2a 1200 1050 ebu e 25 FIG-2b Thecardio-dynamic and anti-arrhythmic properties of this alkaloid areknown, but its oral administration in the form of conventional inorganicsalts of the quinidine base presents the disadvantage of producingcertain disturbances. It is generally recognized that thegastrointestinal disturbances that appear after the use of conventionalcompounds of quinidine are due, in the majority of cases, to a localirritation more than to a systemic toxic manifestation. it is believedthat this irriation is due to the ionic shock that is produced in thegastro-intenstinal mucosa as a consequence of the liberation by rapiddissociation of the irritant ions of the conventional inorganic salts ofthe quinidine base.

The solutions proposed up to now to palliate these disadvantages haveproved to be insufficient. Among the methods that have been suggested toprevent this undesirable effect are the diminution of the dose,

which supposes a diminution of the therapeutic effect; 3

the utilization of parenteral injection, which is troublesome in thecase of prolonged treatments; special enteric coverings of the tablets,which protect the stomach but not the intestine, or the addition ofsubstances which protect the gastric and intestinal mucosa, such asanti-acids or neutralizers.

The purpose of this invention is to reduce the undesirable effectsmentioned, without reducing the therapeutic effect or having recourse totroublesome forms of adminstration.

These and other advantages which will appear in the description thatfollows are achieved by means of the provision of a qunidine salt withpolymanuronic acid, which salt is not very soluble and has a very lowand constant index of dissociation.

Quinidine has proved to be efficacious in patients suffering fromarrhythmic cardiac affections resisting treatment through otheralkaloids derived from quinidine, such as, for instance,dihydroquinidine or quinine.

The polymanuronic acid, which is not dissolved or absorbed in thestomach, becomes slowly dissolved in the intestinal tract. It is endowedwith emollient properties, and increases its volume several times incontact with humidity, for which reason it acts as a protector of thedigestive mucosa, forming a film over the latter and preventing localirritation.

On the other hand, the fact of a slower dissociation of the salt inpolymanuronic acid and quinidine provides a more uniform intestinalabsorption, with more stable and lasting hematic levels of quinidine.This gives it a kind of effect similar to that of depot administration,which undoubtedly facilitates its administration and makes morecomfortable its dosage in the case of patients who habitually shouldhave to take various doses repeated throughout the day and the night.Polymanuronic acid is formed by long polymer chains of manuronic acidcycled in pyranosic form in such a manner that its carboxyl groupsremain free.

COO"

COOH

[t is a relatively strong polyacid, capable of decomposing carbonates,and which can form inorganic and organic salts as well as esters. Thelength of its chain depends on the processes employed in its extractionand purification from certain classes of algae which contain it, and onthe resultant hydrolysis that it undergoes, its molecular weight being,in general, of the order of 240,000, and so it proves to be formed bysome i360 monomer units of manuronic acid.

It is not soluble in water, but on making contact with the latter itswells absorbing from 200 to 300 times its weight in water and forming agel. This gel is not attacked by the gastric juice and dissolves slowlyin the alkaline medium of the intestine.

In the reaction of polymanuronic acid with the quinidine a yellowishodourless powder with a bitter taste is obtained, which decomposes atlC, and which proves to be insoluble in common solvents, except aqueousmethanol and ethanol and propylene glycol.

The empiric formula of the quinidine polymanuronate is (C H O N L thevalue of x depending on the number of monomer units existing in thechain of the acid. The compound presents a content of 60;46% ofquinidine.

The infrared spectrum results characteristic and can be compared withthat of the stoichiometric mixture of quinidine and polymanuronic acid,FIGS. 1, with the compound, FIG. 2, the existence of the latter beingdemonstrated by the peak that is found at l6l5 cm corresponding tocarboxylates and the disappearance of the peak corresponding tocarboxyls and which appears as a broader band towards 1710 cm as well asby its solubility.

Quinidine is soluble in methanol, in ethanol of 96, chloroform,propylene glycol, acetone, etc. Polymanuronic acid is insoluble in thesesolvents, is only very slightly soluble in water, and is soluble insolutions of alkalis and/or carbonates. The compound is insoluble inmethanol, ethanol of 96, chloroform, cold propylene gylcol, acetone,etc., being soluble in methanol and/or ethanol at 50 per cent and in hotpropylene glycol. A simple mechanical mixture of polymanuronic acid andquinidine will consequently partially dissolve the quinidine in one ofthese solvents, while the compound will remain insoluble.

A mechanical mixture of polymanuronic acid and quinidine melts betweenll2 and 1 17C. At this same temperature the polymanuronic acid begins todarken. At 170C the quinidine melts. At 180C the acid ceases to darken,and the compound, which becomes totally decomposed at 190C, commences todarken.

The rotatory power of (C ,,H O,,N is: +77.3 (Propylene glycol, c 0.5).

The preparation of quinidine polymanuronate should be begun with anevaluation of the polymanuronic acid to establish its chemicalequivalent and to know the proportion of quinidine with which it willreact. The course of the reaction can be followed, in addition toobserving the change of aspect of the reacting mixture, by the pH valueswhich, on the termination of the reaction, will be practically neutral.The compound is separated by filtration and is purified by means ofrepeated extractive washings. Finally, the product presents the aspectof a fine dry powder, of slightly yellowish colour, stable in air atambient temperature and up to some 150C.

The reaction between the polymanuronic acid and the quinidine can bebrought about when both compounds are found in a free state, or by meansof a double decomposition between a metal salt of the polymanuronic acidand an appropriate organic and inorganic salt of the quinidine.

Once the polymanuronic acid has been valued and the stoichiometricequivalent of quinidine has been calculated, the product can be obtainedin the following manner:

Polymanuronic acid is suspended in a hydroalcoholic solvent, and to thissuspension there is added, while stirring, an equal volume of the samesolvent containing the necessary quantity of quinidine. The mixture iskept at a moderate temperature and is agitated until the reactionfinalizes. It is then rapidly cooled and filtered. By evaporating thesolvent in vacuum and at the lowest possible temperature, new quantitiesof the compound are recovered. The dry residue is washed with absoluteethanol, is filtered and is again dried.

Once the reaction has terminated, the product may also be isolated byconcentrating it in vacuum until it forms a paste. Then a double volumeof acetone is added, it is cooled, it is left in repose for 24 hours, itis filtered and the product is dried.

Alternatively, it is suspended in water and polymanuronic acid, and tothis suspension, which is heated and stirred, there is added an equalvolume ofa solution of the quinidine necessary in an alcohol of lowmolecular weight. The separation of the product is effected by any ofthe three processes given above.

Again, the polymanuronic acid can be previously dissolved in thenecessary quantity of sodium hydroxide 0,1 N or in another hydroxide,carbonate or bicarbonate of alkaline or alkaline-earth metal.

Instead of the quinidine in its basic form, one of its salts may beemployed with an acid such as sulphuric, hydrochloric, hydrobromic ornitric.

For any process that is followed for obtaining quinidine polymanuronate,the beginning consists of an evaluation of the polymanuronic acid bysuspending in water 0.500 grams of the latter and titrating with sodiumhydroxide 0,1 N, employing phenolphthalein as an indicator.

From this evaluation there is deduced the stoichiometric equivalent ofquinidine for a given quantity of the acid. In the experiment carriedout the equivalence was 10.0 grams of polymanuronic acid for 15.8 gramsof quinidine, and with these quantities the obtention tests were carriedout.

EXAMPLE 1 10 grams of polymanuronic acid are suspended in 400 ml ofmethanol at 50 per cent v/v and, by means ofa funnel fitted with a tap,it is slowly added (the time taken being from one to one and a halfhours) to a suspension of 15.8 grams of quinidine in another 400 m1 ofthe same solvent contained in a 2 litre matrass with reflux refrigerant,and mechanical agitation keeping it in a water bath at C.

The process of reaction, in all cases, should last for a minimum of 2hours, more than three hours not being necessary.

Once the reaction has been completed, the matrass is cooled in a bath ofcrushed ice mixed with sodium chloride to give a temperature of at leastl0C (a refrigerated chamber may also be employed). At the end of some 6hours it is rapidly filtered by means of a Buchner funnel and theproduct is dried at a temperature below C.

The filtered solvent can be employed in a new obtention process, or canbe evaporated by means of a vacuum at a temperature not exceeding 60C,thus recovering a new portion of the product.

The dry residue is washed with absolute ethanol, is filtered and isagain dried.

EXAMPLE 2 In a 2 litre matrass with mechanical agitation and refluxrefrigerant, 10 grams of polymanuronic acid and 400 ml of water areplaced. The matrass is heated in a water bath up to 70 75C, and there isslowly added, by means of a funnel fitted with a tap, 15.8 grams ofquinidine in 400 ml methanol or of ethanol of 96. As in the case of theprevious example, the reaction will be completed in less than threehours.

The reaction mixture is distilled until it reaches the consistancy of apaste at a temperature between 50 and 60C and a pressure of 40 to 60 mmof mercury. To the'residual paste there is added, in cold, a volume ofacetone that is approximately double. The mixture is left overnight inrepose in a refrigerator which maintains it below 5C, it is filtered andthe product is dried.

EXAMPLE 3 Instead of free polymanuronic acid and quinidine which is alsofree, there may be employed one of the sodium, potassium, ammonium ormagnesium salts of polymanuronic acids, and sulphate, nitrate,chlorohydrate or bromohydrate of quinidine, water being employed as asolvent in these cases.

The vessel for the reaction, as well as the technique to be followed,are the same as in the foregoing examples.

The separation of quinidine polymanuronate can also be effected by meansof evaporation of the water and drying of the residue in a centrifugeatomizer at a temperature not exceeding 60C.

The residue is washed with water until the elimination of thecorresponding salt that is formed with the cation of the acid and theanion of the quinidine and after drying it is again washed with absoluteethanol or with acetone.

In all, there are established three processes for obten tion and threeprocesses for separation of the product,

it being possible to employ for its production any of the ninecombinations possible.

I claim:

1. A process for obtaining a salt of polymanuronic acid and quinidine ofthe empirical formula (C H O,,N wherein x is about 1360, which comprisesreacting polymanuronic acid or a metal salt thereof with quinidine orits sulphate, hydrochloride, hydrobromate or nitrate salt instoichiometric amounts at a temperature of between 70C and 75C in thepresence of a solvent, until the pH of the reaction solution is about 7,and isolating the quinidine polymanuronate thus formed.

2. A process in accordance with claim 1, in which the solvent employedis a hydro-alcoholic solvent and the polymanuronic acid and quinidineare employed in the form of a free acid and a free base, respectively.

3. A process in accordance with claim 1, in which the polymanuronic acidis employed in suspension in water, and the quinidine is added insolution in an equal quantity of an alcohol of low molecular weight.

4. A process in accordance with claim 1, in which the polymanuronic acidis employed in the form of its sodium, potassium, ammonium or magnesiumsalt.

5. A process in accordance with claim 1, in which in the appropriatequantity of sodium hydroxide 0.l N sodium hydroxide.

6. A process in accordance with claim 1, in which the quinidine isemployed in the form of its salt with sulphuric, hydrochloric,hydrobromic or nitric acid.

7. A process in accordance with claim 1, in which the solvent is ahydro-alcoholic solvent containing from 40 to 60 percent by volume ofwater and from 40 to 60 percent by volume of an alcohol of up to 4carbon atoms.

8. A process in accordance with claim 1, in which the isolation of theproduct salt is effected by cooling the reaction mixture to below 0C,filtering and drying the product, washing the product with absoluteethanol, and filtering and drying the resultant product.

9. A process in accordance with claim 8, in which the filtrate resultingfrom the first filtering step is evaporated in vacuum at a temperaturedown to 50C to separate an additional quantity of the product salt.

10. A process in accordance with claim 1, in which the isolation of theproduct salt is effected by concentrating the reaction mixture in vacuumuntil a paste is formed therefrom, adding a double volume of acetone tothe paste, cooling the resultant mixture, allowing the cooled mixture tostand for 24 hours, and filtering and drying the resultant product.

11. A process in accordance with claim I, in which the isolation of theproduct salt is effected by evaporating the solvent in a vacuumatomizer, washing the resultant powdered residue with acetone orabsolute ethanol, and filtering and drying the resultant product.

12. A quinidine salt of polymanuronic acid having the followingcharacteristics:

a. fine powder of yellowish color,

b. stable in air at from ambient temperature to about c. empiricalformula (C ,,H O N L, wherein x is about 1360,

d. quinidine content of about 60.46% by weight,

e. infrared spectrum indicating a peak at 1615 cm",

with a broad band at 1710 cm,

f. soluble in 50% methanol, 50% ethanol and hot propylene glycol, andinsoluble in methanol, 96% ethanol, chloroform, cold propylene glycoland acetone,

g. total decomposition at C,

h. rotation of +77.3 (propylene glycol, c=0.5).

1. A process for obtaining a salt of polymanuronic acid and quinidine ofthe empirical formula (C26H32O8N2)x, wherein x is about 1360, whichcomprises reacting polymanuronic acid or a metal salt thereof withquinidine or its sulphate, hydrochloride, hydrobromate or nitrate saltin stoichiometric amounts at a temperature of between 70*C and 75*C inthe presence of a solvent, until the pH of the reaction solution isabout 7, and isolating the quinidine polymanuronate thus formed.
 2. Aprocess in accordance with claim 1, in which the solvent employed is ahydro-alcoholic solvent and the polymanuronic acid and quinidine areemployed in the form of a free acid and a free base, respectively.
 3. Aprocess in accordance with claim 1, in which the polymanuronic acid isemployed in suspension in water, and the quinidine is added in solutionin an equal quantity of an alcohol of low molecular weight.
 4. A processin accordance with claim 1, in which the polymanuronic acid is employedin the form of its sodium, potassium, ammonium or magnesium salt.
 5. Aprocess in accordance with claim 1, in which in the appropriate quantityof sodium hydroxide 0.1 N sodium hydroxide.
 6. A process in accordancewith claim 1, in which the quinidine is employed in the form of its saltwith sulphuric, hydrochloric, hydrobromic or nitric acid.
 7. A processin accordance with claim 1, in which the solvent is a hydro-alcoholicsolvent containing from 40 to 60 percent by volume of water and from 40to 60 percent by volume of an alcohol of up to 4 carbon atoms.
 8. Aprocess in accordance with claim 1, in which the isolation of theproduct salt is effected by cooling the reaction mixture to below 0*C,filtering and drying the product, washing the product with absoluteethanol, and filtering and drying the resultant product.
 9. A process inaccordance with claim 8, in which the filtrate resulting from the firstfiltering step is evaporated in vacuum at a temperature down to -50*C toseparate an additional quantity of the product salt.
 10. A process inaccordance with claim 1, in which the isolation of the product salt iseffected by concentrating the reaction mixture in vacuum until a pasteis formed therefrom, adding a double volume of acetone to the paste,cooling the resultant mixture, allowing the cooled mixture to stand for24 hours, and filtering and drying the resultant product.
 11. A processin accordance with claim 1, in which the isolation of the product saltis effected by evaporating the solvent in a vacuum atomizer, washing theresultant powdered residue with acetone or absolute ethanol, andfiltering and drying the resuLtant product.
 12. A QUINIDINE SALT OFPOLYMANURONIC ACID HAVING THE FOLLOWING CHRACTERISITICS: A. FINE POWDEROF YELLOWISH COLOR, B. STABLE IN AIR FROM AMBIENT TEMPERATURE TO ABOUT150*C, C.EMPIRICAL FORMULA (CH26H32O8N2)X, WHEREIN X IS ABOUT 1360, D.QUINIDINE CONTENT OF ABOUT 60.46% BY WEIGHT, E. INFRARED SPECTRUMINDICATING A PEAK AT 1615 CM-1, WITH A BROAD BAND AT 1710 CM-1, F.SOLUBLE IN 50% METHANOL, 50% ETHANOL AND HOT PROPYLENE GLYCOL, ANDINSOLUBLE IN METHANOL, 96% ETHANOL, CHLOROFORM, COLD PROPYLENE GLYCOLAND ACETONE, G. TOTAL DECOMPOSITION AT 190*C, H. ROTATION OF +77.3*(PROPYLENE GYCOL,C=0.5).